Project Summary/Abstract: Our proposal consists of a Placebo controlled trial of dextromethorphan in Rett syndrome to be conducted at the Kennedy Krieger Institute (KKI)/Johns Hopkins Medical Institutions (JHMI). RTT is a neurodevelopmental disorder with devastating consequences on both brain and systemic neurons. Girls with RTT have seizures and hyperkinetic movements suggesting excessive excitatory neuronal activity, and the levels of the excitatory neurotransmitter, glutamate, in cerebrospinal fluid are elevated. Brain magnetic resonance spectroscopy (MRS) also shows high levels of glutamate. Neurotransmitter autoradiography of postmortem frontal cortex from girls less than 8 years of age with RTT showed a significant increase in NMDA-type (N-methyl-D-aspartate) glutamate receptors despite a 50% reduction in the number of synapses. Additionally, our in vitro studies of cultured neurons from mice with a mutation in the MECP2 gene show that they are abnormally sensitive to hypoxia and glutamate mediated excitotoxicity. Electrophysiologic studies of these mice show enhanced excitability in the hippocampus and rhythmic discharges in cortex on EEG. As DM competitively blocks NMDA receptor channels, we propose that it will improve the clinical manifestations of RTT (abnormal behaviors, cognitive deficits, neurophysiological abnormalities, and seizures) by reducing excitatory synaptic activity thereby rescuing brain tissue from excitotoxicity. Presently, RTT has no cure. Our objective is to test the efficacy and safety of DM in RTT to improve communication and alleviate behavioral and physical symptoms. Towards this goal, the outcome measures are: Primary outcome: Improvement in the receptive language age equivalent scores on the Mullen scale; Secondary outcomes: a) Improvement in other subscales of the Mullen; b) Improvement in the Socialization and Communication scales of Vineland Adaptive Behavior; c) Improvement in the Ghuman- Folstein Screen for Social Interaction. Exploratory variables are a) Change in the Aberrant Behavior Checklist scores; b) Rett Syndrome Behavior Questionnaire; c) EEG and MisMatch Negativity; d) Quality of Life Questionnaire. A total of 60 subjects who are fast metabolizers of DM, with clinical features of RTT and a known mutation in the MECP2 gene, will be equally randomized in a double-masked trial to placebo or treatment with 5mg dextromethorphan /kg/day for twelve weeks using a blocked and stratified (for age and the presence of seizures) randomization. Analyses will be done on an intention-to-treat basis. Our previous study showing improved alertness and social interaction on neuropsychological and behavioral assessments is encouraging.